Stromal-induced Epithelial-mesenchymal Transition Induces Targetable Drug Resistance in Acute Lymphoblastic Leukemia

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2023 Jul 15

PMID 37453060

Authors

Chun Shik Park

Hiroki Yoshihara

Qingsong Gao

Chunxu Qu

Ilaria Iacobucci

Pankaj S Ghate

Jon P Connelly

Shondra M Pruett-Miller

Ben Wagner

Camenzind G Robinson

Ashutosh Mishra

Junmin Peng

Lei Yang

Zoran Rankovic

David Finkelstein

Selina Luger

Mark Litzow

Elisabeth M Paietta

Nikhil Hebbar

M Paulina Velasquez

Charles G Mullighan

Affiliations

Soon will be listed here.

Abstract

The bone marrow microenvironment (BME) drives drug resistance in acute lymphoblastic leukemia (ALL) through leukemic cell interactions with bone marrow (BM) niches, but the underlying mechanisms remain unclear. Here, we show that the interaction between ALL and mesenchymal stem cells (MSCs) through integrin β1 induces an epithelial-mesenchymal transition (EMT)-like program in MSC-adherent ALL cells, resulting in drug resistance and enhanced survival. Moreover, single-cell RNA sequencing analysis of ALL-MSC co-culture identifies a hybrid cluster of MSC-adherent ALL cells expressing both B-ALL and MSC signature genes, orchestrated by a WNT/β-catenin-mediated EMT-like program. Blockade of interaction between β-catenin and CREB binding protein impairs the survival and drug resistance of MSC-adherent ALL cells in vitro and results in a reduction in leukemic burden in vivo. Targeting of this WNT/β-catenin-mediated EMT-like program is a potential therapeutic approach to overcome cell extrinsically acquired drug resistance in ALL.

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